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TREX tetramer disruption alters RNA processing necessary for corticogenesis in THOC6 Intellectual Disability Syndrome
Elizabeth A Werren1,2, Geneva R LaForce3, Anshika Srivastava1,4
1Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
Nature Communications
|February 22, 2024
Summary
Genetic variants in THOC6 cause autosomal recessive THOC6 Intellectual Disability Syndrome (TIDS). This study reveals THOC6
Area of Science:
- Molecular Biology
- Genetics
- Neurodevelopmental Biology
Background:
- THOC6 variants are identified as the genetic cause of autosomal recessive THOC6 Intellectual Disability Syndrome (TIDS).
- THOC6 plays a crucial role in the formation of the mammalian Transcription Export complex (TREX) tetramer, essential for RNA processing and nuclear export.
Purpose of the Study:
- To investigate the function of THOC6 in mammalian RNA processing and its role in TIDS.
- To elucidate the species-specific functions of the TREX tetramer mediated by THOC6.
Main Methods:
- Utilized human and mouse model systems for TIDS.
- Analyzed the impact of biallelic Thoc6 loss-of-function (LOF) variants on TREX complex formation and RNA processing.
- Examined THOC6's role in neural cell function and corticogenesis signaling pathways.
Main Results:
- Biallelic THOC6 LOF variants lead to reduced ALYREF binding to THOC5, indicating impaired TREX tetramer formation.
- Contrary to nuclear export defects, mis-splicing was observed in human and mouse neural tissues, highlighting THOC6-mediated mRNA processing.
- THOC6 is essential for signaling pathways regulating the transition from proliferative to neurogenic divisions in human corticogenesis.
Conclusions:
- THOC6 is critical for novel, species-specific functions of the TREX tetramer, particularly in mRNA processing.
- Altered RNA processing due to THOC6 dysfunction is implicated in the neuropathology of TIDS.
- These findings reveal a new mechanism of THOC6 in neurodevelopment and intellectual disability.
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